DESCRIPTION: Photoimmunotherapy involves the administration of a photosensitizer conjugated to monoclonal antibodies followed by light activation of the photoimmunoconjugate. The systemic toxicity associated with radio- and chemo-immunoconjugates may thus be significantly reduced in photoimmunotherapy due to the dual selectivity provided by the tumor localizing Mab and the spatial control of illumination. The goal of this research is to optimize photo-immunotherapy for the destruction of minimal residual ovarian cancer. Both the size and charge of photoimmunoconjugates will be varied to determine the affect of these properties on the degree to which the immunoconjugate binds to and penetrates the tumor. A conjugation strategy has been developed which produces photoimmunoconjugates which retain their antigen recognition capacity, are covalently bound to many photosensitizer molecules, and can bear different numbers of positive or negative charges. This involves the site-specific attachment of modified polylysine chains bearing chlorin e6 molecules to the F(ab')2 fragment of the anti-ovarian cancer Mab, OC125. These photo-immunoconjugates will be characterized as to their substitution ratios, size, charge, and interactions with both target and non-target cells in vitro. The photoimmunoconjugates will be compared to non-specific rabbit IgG photo-immunoconjugates and to the polylysine conjugates alone. in vivo photoimmuno-therapy will be investigated in a newly developed nude mouse xenograft model of human ovarian cancer. The strategy will be: (i) to establish the best ce6-based photoimmunoconjugate and the optimal conditions for its administration. This will be done by investigating the pharmacokinetics and biodistribution after i.p. administration of radiolabelled photoimmunoconjugates. Minimally invasive techniques (laser induced fluorescence and in vivo scanning microscopy) and destructive techniques (tissue sectioning for fluorescence microscopy and autoradiography, and photosensitizer extraction) on the same tumor and normal tissue samples will give information on the tumor to normal ratios, maximal tumor content and depth of penetration; (ii) to treat the mice at the maximum tolerated doses of both photosensitizer and light. Short term (1 week) reduction in tumor burden will be followed for the photoimmunoconjugates of different charge; (iii) when the optimum photoimmunoconjugate and treatment schedule have been identified, the mice will be treated in groups by photoimmunotherapy, photodynamic therapy with an established modality (BPD-MA) and combination chemotherapy with taxol/cisplatin, and the long term survival will be followed; and (iv) the optimal photoimmunoconjugate will be prepared using BPD-MA as the photosensitizer bound to the F(ab')2, and this photoimmunoconjugate will be compared to BPD-MA to test the efficacy of photoimmunotherapy. It is expected that these studies will lead to a fundamental understanding of the role of size and charge in determining the degree to which photoimmunoconjugates penetrate tumors and will give a measure of the efficacy of i.p. photoimmunotherapy in comparison with standard PDT and chemotherapy.